Characterization of human cytokine-producing B cells in Sjogren's Syndrome

描述(由申请者提供)：这个有指导的临床科学家发展奖将为James M.Roger博士提供必要的支持，使他能够继续他的培训，从最近的牙科学校毕业生(DOS，2008)到免疫学博士，并以追求学术生涯为长期目标。罗杰博士的培训将在共同导师伊格纳西奥·桑兹博士和詹姆斯·E·梅尔文博士的指导下进行。在开始他的研究生论文项目的教学和初步实验后，他将专注于研究干燥综合征(SS)中B细胞产生细胞因子。腺体破坏导致口干和眼干的显著症状与炎症和淋巴细胞渗入有关。最近在B细胞耗竭治疗方面的研究表明，B细胞在自身免疫中起着中心致病作用，并进一步观察到B细胞通过产生细胞因子等“非抗体”手段促进疾病进展。已观察到人类SS和小鼠模型中的B细胞能产生多种细胞因子，如IL-10、IL-6、肿瘤坏死因子-α和干扰素-α。虽然B细胞能够在SS的腺体局部和血液中系统地产生各种细胞因子的观察是有趣的，但有人提出了一种系统的方法来剖析这些产生细胞因子的B细胞的功能，以进一步确定它们的效应功能。罗杰博士将验证这一假设，即产生细胞因子的B细胞通过全身炎症调节和靶组织在三个特定目标上的影响而对SS做出贡献。目的1：描述当地健康人群中细胞因子和产生细胞因子的B细胞群的特征。目的2：研究SS患者局部队列中细胞因子和产生细胞因子的B细胞群的特征。目的：探讨浸润性B细胞在SS涎腺病变过程中的作用。 公共卫生相关性：干燥综合征是最常见的自身免疫性疾病之一，估计有1-4%的美国人口和女性与男性的比例为9：1。通过确定B细胞在SS与健康患者中的作用，未来可能开发出新的、特定的SS筛查工具和治疗方法。最后，这一奖项将为罗杰博士提供必要的工具，以准备更高级的拨款申请，从而进入学术研究生涯。

DESCRIPTION (provided by applicant): This Mentored Clinical Scientist Development Award will provide Dr. James M. Roger the support necessary for him to continue his training from that of a recent dental school graduate (DOS, 2008) towards a PhD in Immunology with the long term goal of pursuing an academic career. Dr. Roger's training will be under the guidance of co-mentors, Dr. Ignacio Sanz and Dr. James E. Melvin. Having begun the didactic and preliminary experiments of his graduate thesis project, he will focus his efforts on studying cytokine production by B cells in Sjogren's Syndrome (SS). The hallmark symptoms of glandular destruction leading to dry mouth and dry eye are associated with inflammation and infiltrating lymphocytes. Recent studies in B cell depletion therapy have suggested a central pathogenic role for B cells in autoimmunity as well as further observations that B cells contribute to disease progression by "antibody independent" means such as cytokine production. B cells in human SS as well as mouse models have been observed to produce a diverse array of cytokines such as, IL-10, IL-6, TNF- Ipha, and IFN- amma. While the observation that B cells are capable of producing a variety of cytokines both locally in the gland and systemically in the blood in SS is intriguing, a systematic approach to dissect the function of these cytokine producing B cells is proposed to further define their effector function. Dr. Roger will test the hypothesis that cytokine-producing B cells contribute to SS through systemic inflammatory modulation and target-tissue influences in three specific aims. Aim 1: Characterization of the cytokines and cytokine-producing B cell populations in a local cohort of healthy subjects. Aim 2: Characterize the cytokines and cytokine-producing B cell populations in a local cohort of SS patients. Aim 3: Examine the involvement that infiltrating B cells play in the disease process in SS salivary glands. Public Health Relevance: Sjogren's Syndrome is one of the most common autoimmune diseases afflicting an estimated 1-4% of the US population and women to men in a ratio of 9:1. By characterizing the role of B cells in the SS versus the healthy patient, it may be possible to develop new and specific screening tools and treatments for SS in the future. Finally, this award will provide Dr. Roger the tools necessary to prepare more advanced grant submissions leading to a career in academic research.